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Abstract:

The present invention relates to a medical device of an endoscopic type
providing a visually observable image of an examination area in an
interior of an organism, which is typically used in the medical field for
diagnostic purposes. The present invention is intended for the minimally
invasive in-situ examination and analysis of organs and tissues
preferably in the interior of a living human being or animal.

Claims:

1. An endoscopic device comprisingan imaging unit for the generation of a
visually observable image of an examination area in an interior of an
organism, anda bioanalytical unit for the qualitative or quantitative
analysis of at least one physiological or pathological parameter in a
definable area of interest within the examination area,wherein the area
of interest for the qualitative or quantitative analysis of the at least
one physiological or pathological parameter can be defined under visual
control with the aid of the generated visually observable image.

2. An endoscopic device of claim 1, wherein the bioanalytical unit
comprises an in situ sensor, a spectroscopic means or both for the
qualitative or quantitative analysis of at least one physiological or
pathological parameter.

3. An endoscopic process comprising the steps of:generating a visually
observable image of an examination area in an interior of an organism by
an imaging unit,defining an area of interest within the examination area
under visual control with the aid of the generated visually observable
image, andanalyzing at least one physiological or pathological parameter
in said definable area of interest by a bioanalytical unit.

4. An endoscopic process according to claim 3, wherein in the analyzing
step the bioanalytical unit detects the presence, absence, concentration,
or modification of at least one biomarker or the concentration ratio of
at least two biomarkers by means of at least one of an in situ sensor, a
spectroscopic means, or both.

5. An endoscopic device according to claim 1, wherein the bioanalytical
unit comprises at least one in situ chemical or biochemical or
immunological sensor, or a sensor array of such sensors.

6. An endoscopic device according to claim 5, wherein the bioanalytical
unit comprises an in situ SPR (surface plasmon resonance) sensor or a
sensor array of such sensors, or wherein the bioanalytical unit comprises
a spectroscopic analysis device.

7. An endoscopic device of claim 6, wherein the spectroscopic analysis
device is a Raman spectroscopic analysis device or a fluorescence
spectroscopic device.

8. An endoscopic process according to claim 3, further comprising the
steps of: applying a dissolved, emulsified or suspended biochemical,
chemical and/or immunological agent or micro- or nano-spheres or micro-
or nano-particles comprising a biochemical, chemical and/or immunological
agent, wherein said agent is analyzable by the bioanalytical unit.

9. An endoscopic device according to claim 1, further comprising a drug
application unit for the controllable release of a defined quantity of a
diagnostic and/or therapeutic drug or other agent into a defined
diagnostic and/or therapeutic target area.

10. An endoscopic device according to claim 9, wherein the therapeutic
drug is releasable or activatable by irradiation with laser light.

11. An endoscopic device according to claim 1, further comprising a
therapeutic unit for treating and/or destroying and/or removing tissue
from the therapeutic target area.

12. An endoscopic process according to claim 3, further comprising the
step of releasing or activating a therapeutic drug in a therapeutic
target area by irradiation with laser light, by means of a surgical
laser, or both.

13. An endoscopic process according to claim 3, further comprising the
steps ofapplying a dissolved, emulsified or suspended biochemical,
chemical and/or immunological agent; micro- or nano-spheres or micro- or
nano-particles comprising a biochemical, chemical or immunological agent;
or a combination thereof; andsubsequently analyzing said agent by the
bioanalytical unit.

14. An endoscopic process according to claim 3, further comprising the
step of releasing a defined quantity of a diagnostic or therapeutic drug
or other agent into a defined diagnostic or therapeutic target area by a
drug application unit.

15. An endoscopic process of claim 14, wherein the therapeutic agent
comprises a drug being bound to or contained in a drug carrier or an
activatable inactive drug, or wherein the therapeutic drug is released or
activated in a therapeutic target area by irradiation with laser light.

16. An endoscopic process according to claim 3, further comprising the
steps ofdefining a therapeutic target area andtreating, destroying or
removing tissue from the therapeutic target area by means of releasing or
activating a therapeutic drug in a therapeutic target area through
irradiation with laser light, by means of a surgical laser, or both.

[0002]The present invention relates to a medical device of an endoscopic
type providing a visually observable image of an examination area in an
interior of an organism, which is typically used in the medical field for
diagnostic purposes. The present invention is intended for the minimally
invasive in-situ examination and analysis of organs and tissues
preferably in the interior of a living human being or animal.

BACKGROUND OF THE INVENTION

[0003]During the last decades, such endoscopic devices have gained
increasing importance in medical diagnosis of diseases, in particular of
injuries, degenerative and tumor diseases. In particular in tumor
diagnosis e.g. of the colon colonoscopic examination by endoscopes has
become the standard diagnostic method.

[0004]A typical prior art endoscope comprises at least: [0005]a rigid or
flexible tube, which is inserted into the interior of the organism and
advanced to the organs and/or specific tissues to be examined
(examination area); [0006]a light delivery system to illuminate the
examination area, i.e. the organ, tissue or object under inspection. The
light source is normally outside the body and the light is typically
directed to the examination area via an optical fiber system extending
through the rigid or flexible tube; [0007]an optical and/or
optoelectronic system (imaging unit) which gathers and transmits the
endoscopic image of the interior of the organism to the viewer from the
endoscope, typically a medical professional who uses this endoscopic
image for his/her diagnosis; [0008]an additional channel (working
channel) to allow for example the entry of surgical or other medical
instruments or manipulators for example for taking tissue samples which
can be examined and analyzed histologically or histochemically in a
laboratory after the endoscopic intervention.

[0009]Endoscopes can generally be divided into two parts, one
part--subsequently called "nosepiece", comprising a substantial part of
the rigid or flexible tube--which is introduced into a natural or
artificial cavity or orifices of the organism, whereas the remainder of
the device--subsequently called "eyepiece"--stays outside of the organism
and is typically fixed e.g. to a laboratory rack or other type of
support. Usually, amongst others, light sources, optical components for
the spectral manipulation or analysis of light, devices for processing
the electronically converted image and the sensor signals and other
components--which cannot reside in the nosepiece--are accommodated in the
eyepiece. Nosepiece and eyepiece are in constant physical connection with
each other and typically electrical and/or optical signals are exchanged
between both parts.

[0010]The diameter of the nosepiece is typically small (usually in the
range of a few millimeters) and outer shape and dimension of the
nosepiece is designed to fit into said cavities or orifices in order to
prevent or minimize lesions. The image acquisition at the tip of the
nosepiece and the image transmission to the eyepiece can occur optically
(by means of an imaging optics projecting the image of the area under
examination (examination area) onto the aperture of an optical fiber
bundle wherein each fiber of the optical fiber bundle gathers and
transmits one pixel of this image to the eyepiece, or by means of a lens
system distributed over the length of the nosepiece typically producing a
plurality of virtual intermediate images thus bridging the distance from
the tip of the nosepiece to the eyepiece) or otherwise
opto-electronically (by means of a sensor array, e.g. a CCD sensor array,
being located in the tip region of the nosepiece and transmitting the
image data electrically to the eyepiece). In most modern endoscopes the
optical image is converted to an electronic signal (either in the tip
region of the nosepiece or in the eyepiece) which is subsequently
electronically processed and displayed by a monitor.

[0011]In case of the afore-mentioned colonoscopy, the nosepiece of the
endoscope is inserted into the colon thereby providing an image of the
intestinal mucosa while the nosepiece is further advanced through or
retracted from the colon. The medical professional who is trained to
colonoscopic methods, is able to localize and identify suspicious spots
in the intestinal mucosa which may indicate a degeneration, neoplasm or
cancerous alteration of tissue. To further consolidate this visual
diagnosis the medical professional will take tissue samples of the
suspicious tissue spots, which are excised by surgical instruments and
dispatched via the working channel of the endoscope. After the endoscopic
intervention the tissue samples are examined histologically and/or
histochemically in a specialized histological laboratory, which may take
several days or weeks until the diagnosis can be confirmed or rebutted.
In case of a positive histological or histochemical result a second
surgical or endoscopic intervention will be necessary.

[0012]This time of waiting for the histological or histochemical results
and the final diagnosis and the thereby imposed uncertainty about the
findings and the potential necessity of a second surgical or endoscopic
intervention are very stressful for the patient. In some cases, the loss
of time for confirming the diagnosis required by the examination in the
histological or histochemical laboratory may be harmful if the tumor is
fast-growing and further proliferates and spreads. As an additional
aspect, the classical endoscopic examination techniques require of the
medical professional a long training and practice in this field which
implies that the reliability and accuracy of the diagnoses largely
depends on the experience of the medical professional. Thus, a medical
professional who is not experienced in this field may produce a
significant percentage of wrong-positive and wrong-negative diagnoses.

BRIEF SUMMARY

[0013]The technology described relates to an endoscopic medical device and
endoscopic process that provides a visually observable image of an
examination area in an interior of an organism, which is typically used
in the medical field for diagnostic purposes. The devices and processes
are used in minimally invasive in-situ examinations and analyses of
organs and tissues, such as in the interior of a living human being or
animal.

[0014]One example endoscopic device includes an imaging unit for the
generation of a visually observable image of an examination area in an
interior of an organism and a bioanalytical unit for the qualitative
and/or quantitative analysis of a physiological and/or a pathological
parameter in a definable area of interest within the examination area.
The area of interest for the qualitative and/or quantitative analysis of
the physiological and/or pathological parameter can be defined under
visual control with the aid of the generated visually observable image.
Further, the bioanalytical unit can include an in situ sensor, a
spectroscopic means or both for the qualitative and/or quantitative
analysis of a physiological and/or pathological parameter.

[0015]An example endoscopic process includes generating a visually
observable image of an examination area in an interior of an organism by
an imaging unit. The process also includes defining an area of interest
within the examination area under visual control with the aid of the
generated visually observable image, and analyzing at least one
physiological or pathological parameter in the definable area of interest
with a bioanalytical unit.

BRIEF DESCRIPTION OF THE DRAWING

[0016]In the following description, the invention is further explained by
means of exemplary embodiments in conjunction with the accompanying
drawing, in which:

[0017]FIG. 1 shows a schematic diagram of the tip of the nosepiece
according to an embodiment of the present invention.

DETAILED DESCRIPTION

[0018]It is therefore an object of the present invention to provide an
endoscopic device and a corresponding process which allows a quick and
reliable in-situ diagnosis of tissue alterations as well as of diseases
and conditions of organs and/or tissues under examination.

[0019]For the endoscopic device, this object is achieved by an endoscopic
device comprising [0020]an imaging unit for the generation of a
visually observable image of an examination area in an interior of an
organism, and [0021]a bioanalytical unit for the qualitative and/or
quantitative analysis of at least one physiological or pathological
parameter in a definable area of interest within the examination area,
preferably by means of an in-situ sensor and/or by means of spectroscopy,
[0022]wherein the area of interest for the qualitative and/or
quantitative analysis of the at least one physiological or pathological
parameter can be defined under visual control with the aid of the
generated visually observable image.

[0023]Concerning the endoscopic process, the object is solved by an
endoscopic process comprising the steps of: [0024]generating a visually
observable image of an examination area in an interior of an organism by
an imaging unit, [0025]defining an area of interest within the
examination area under visual control with the aid of the generated
visually observable image, and [0026]analyzing at least one physiological
or pathological parameter in said definable area of interest by a
bioanalytical unit, preferably by means of at least one in-situ sensor
and/or by means of spectroscopy.

[0027]It is an advantage of the inventive endoscopic device and the
inventive endoscopic process that the reliability of diagnoses can be
increased independent of the experience of the medical professional
carrying out the examination. Furthermore, the repertoire of diagnostic
methods is increased and additional diagnostic facilities and options are
made accessible. As a further advantage, loss of time by waiting for the
histological and/or histochemical laboratory results can be eliminated,
which means earlier and more successful treatment of the disease and less
stress for the patients. Additionally, a further surgical intervention,
another anesthesia and another surgical traumatization of the patient may
be avoided. Also the problem of common prior art endoscopy--that the
potentially pathological spots identified during the first endoscopic
examination and confirmed by the laboratory result have to be
re-localized during a second surgical intervention--may be avoided as the
endoscopic device and method of this invention offers the possibility of
treating pathological alterations immediately after their identification
and diagnostic evaluation in a single diagnostic and therapeutic
appointment. As a consequence, by the inventive endoscopic device and
process costs for the medical treatment can be saved and quality of the
medical treatment can be improved.

[0028]In a preferred embodiment of the endoscopic device or process, the
presence, absence, concentration, and/or modification of at least one
biomarker and/or the concentration ratio of at least two biomarkers may
be detectable by the bioanalytical unit.

[0029]For example it may be possible to detect and measure the
concentration of biomarkers being endogenously produced in the body by
one or more sensors or transducers or by spectroscopic methods wherein
this information revealed by the biomarker is an indicator for a
physiological or pathological condition.

[0030]An example for such biomarkers may be sTNFR (soluble tumor necrosis
factor receptors) that are emitted by the tumor cells to inactivate TNF
molecules that originate from the immune system. The presence of sTNFR is
therefore a strong hint for cancer, and its concentration is much higher
in close proximity to a tumor.

[0031]It is further possible to correlate for example the detected
concentration of one biomarker to one or more other parameters, or for
example to the concentration of a second biomarker, for example by
subtracting, dividing or other mathematical calculations of the measured
parameters. By this, for example, a baseline or a ratio could be formed,
artifacts or natural variabilities of anatomical and/or physiological
nature can be eliminated and/or the diagnostic reliability can be
increased.

[0032]Two (or more) measurements of biomarkers can be carried out either
with a one-fiber bioanalytical unit or with a multi-fiber bioanalytical
unit, or, due to the modular design of the device, with two (or more)
independent bioanalytical units (that might share some instrumentation in
the eyepiece).

[0033]Thus, by providing a bioanalytical unit which can detect the
presence, absence, concentration, and/or modification of at least one
biomarker and/or the concentration ratio of at least two biomarkers it is
possible to directly analyze endogenous molecules and to use this
information for making reliable diagnoses.

[0034]In a preferred embodiment of the endoscopic device or process the
bioanalytical unit may comprise at least one in-situ chemical or
biochemical or immunological sensor, preferably biosensor, or sensor
array. This could, for example, be individual sensors or one-dimensional
or two-dimensional arrays or configurations of such sensors which may
detect and convert a chemical or biochemical or immunological parameter
at the tip of the nosepiece into preferably an electrical or optical
signal which may be analyzed in the eyepiece. Preferable types of sensors
may be electrochemical sensors, piezoelectric sensors, or semiconductor
sensors, electrooptical sensors or surface plasmon resonance (SPR)
sensors. By such embodiments, the measured parameter can be analyzed
quantitatively in a selective spot at the tip of the nosepiece with an
increased accuracy.

[0035]As an example, it is possible to prepare a glass surface (e.g. at
the tip of one or more of the fibers of the bioanalytical unit) with a
grid of antibody molecules that specifically bind to certain cancer
cells. If cancer cells bind to the prepared surface, this can be revealed
by different kinds of spectroscopic methods, e.g. by fluorescence
spectroscopy. In this case, the fluorescence signal arises directly from
the fiber tip and fluorescence light will couple back into the fiber with
a good efficiency and reach the detector unit.

[0036]In a preferred embodiment of the endoscopic device or process the
bioanalytical unit may comprise an in-situ SPR (surface plasmon
resonance) sensor or sensor array. By providing a bioanalytical unit
working with the SPR method, it is possible to detect or determine a
variety of physiological or pathological parameters for example via
appropriate biomarkers e.g. by means of highly selective antibodies with
a very high selectivity and reliability.

[0037]Such SPR sensor may comprise a glass or transparent resin surface
(again either at the tip or in a circumferential area of the fiber, or at
a flat beveled part of the fiber side) which surface is coated with a
thin (nanometer range) layer of a metal or metal oxide (typically gold,
other noble metals or conducting metal oxides) and a grid of antibody
molecules wherein the antibody molecules are designed to bind to cells,
cell fragments or molecules of which the concentration is to be measured.
Upon binding, the refractive index of the antibody layer may change. As
is known in the art about the SPR method, light that is totally reflected
at the back side of the metal or metal oxide layer, will also couple to
its front side by generation of surface plasmons (evanescent wave
coupling) which leads to a partial frustration of the total reflection
that can be measured and converted to a measurement value of e.g. cell or
molecule concentrations.

[0038]In a preferred embodiment of the endoscopic device or process the
bioanalytical unit may comprise a spectroscopic analysis device,
preferably a Raman spectroscopic analysis device or a fluorescence
spectroscopic device. By providing a bioanalytical unit with a
spectroscopic analysis device it is possible on the one hand to
selectively measure one spot--directly at the end of the nosepiece or
distant from the end of the nosepiece in the sample--with an increased
sensitivity and accuracy. On the other hand the bioanalytical unit may be
designed to capture an image (still image, intervallic image sequence or
movie) of a larger area providing for example a two- or
three-dimensionally spatially dissolved image of the anatomic structures
by spectroscopic imaging methods which allows an overview about the area
of interest for assessing the dimension and the borders for example of a
pathologic alteration. Such suitable spectroscopic methods may comprise
in particular fluorescence spectroscopy (single photon or multi photon),
absorption spectroscopy, e.g. infrared spectroscopy, UV/VIS
(ultraviolet/visible light) spectroscopy, Raman spectroscopy or SPR
spectroscopy.

[0039]For example fluorescence spectroscopy can be used with (either
intrinsic or extrinsic) dyes where for example heights of characteristic
peaks in the emission spectra, shifts in the emission spectra (in
particular in the peak region) or ratios of spectral intensities at
characteristic wavelengths can be measured and analyzed allowing the
calculation of concentrations of said dyes. Some dyes can furthermore be
used as molecular probes which monitor the presence, absence,
concentration, and/or modification of an effector (for example pH, oxygen
concentration, inorganic molecules, organic molecules or biomolecules)
which specifically binds to said dye. Other dyes may be used to
selectively stain specific tissue structures. Furthermore, differences in
autofluorescence spectra may be used to characterize tissue type. It is
also possible to use Raman spectroscopy to detect extrinsic markers that
are manufactured to bind to cancer cells. Those markers could contain a
metal like gold, or heavy water (hydrogen replaced by deuterium), which
generates Raman spectra with large peaks that differ significantly from
that of the surrounding tissue. E.g., heavy water enriched biomolecules
show a distinct peak in the Raman spectrum at about 2100 cm-1
(carbon-deuterium stretch vibration) which does not exist in "normal"
biological matter (which show a large peak at about 2850 cm-1 for
the carbon-hydrogen stretch vibration).

[0040]It is also conceivable to provide two or more bioanalytical units
working on the basis of the same or different measuring principles in the
endoscopic device measuring different parameters in order to e.g.
eliminate or reduce artifacts or natural variabilities or to allow
differential diagnoses with increased diagnostic reliability. The
bioanalytical units may either be installed permanently in the nosepiece
or be introduced temporarily through the working channel e.g. only when
needed. In this context, it may also be conceivable to decide during the
endoscopic examination whether and which type(s) of bioanalytical unit(s)
shall be applied depending e.g. on the discovered alterations or on
medical or diagnostic requirements of the application. After completion
of the measurement, the bioanalytical unit may be removed from the
working channel in order to clear the working channel for other purposes
(e.g. for other analytical instrumentation or surgical endoscopic
instruments). It is furthermore possible to use several types of
bioanalytical units sequentially, or to regenerate or to replace the
sensors of the bioanalytical unit after each application or measurement.

[0041]In a preferred embodiment of the endoscopic device an agent,
preferably a dissolved, emulsified or suspended biochemical, chemical
and/or immunological agent and/or micro- or nano-spheres or micro- or
nano-particles comprising a biochemical, chemical and/or immunological
agent may be applicable, wherein said agent is analyzable by the
bioanalytical unit, preferably by the spectroscopic analysis device.

[0042]In a preferred embodiment the endoscopic process may further
comprise the steps of [0043]applying an agent, preferably a dissolved,
emulsified or suspended biochemical, chemical and/or immunological agent
and/or micro- or nano-spheres or micro- or nano-particles comprising a
biochemical, chemical and/or immunological agent, and [0044]subsequently
analyzing said agent by the bioanalytical unit, preferably by the
spectroscopic analysis device.

[0045]Such agent could be a diagnostic agent (for example extrinsic dyes
or markers) enlarging the range of applications and measurement
possibilities. By applying such agent, the range of detectable
substances, parameters, biomarkers or cell types can be increased and
reliability and accuracy of diagnosis can be improved.

[0046]For example extrinsic markers may be applied to the area of interest
before the area is analyzed spectroscopically. In general, extrinsic
markers may be used because (i) they share the position with the target
(by detecting the marker, the target can easily be identified), providing
the advantage that molecules or cells can be measured which otherwise
could only difficultly or imprecisely or not at all be measured; (ii)
extrinsic markers are under control of the measurement process whereas
intrinsic markers are, by their nature, not (e.g., fluctuations within
the sample, changes across a population of patients); (iii) biochemical
or immunological binding behavior can be engineered for high specificity
(e.g. antigen-antibody link) and (iv) extrinsic markers can be engineered
for specific spectroscopic properties, e.g. tuned to show certain peaks
in fluorescence or Raman spectrum that can be detected reliably and
precisely even in low concentrations and in presence of a multitude of
other molecules or cells.

[0047]Among the preferred extrinsic markers are: (i) fluorescent dyes
linked to biomolecules or antibodies that bind to, e.g., either membrane
proteins which are specific to cancer cells, or to soluble tumor markers
like sTNFR (soluble tumor necrosis factor receptors) molecules mentioned
above, or specifically designed markers for Raman spectroscopy as
mentioned above or dye molecules with a specific binding site e.g. for
inorganic, organic or biochemical molecules; (ii) spheres with a diameter
between the low micrometer and the middle to large nanometer range, made
from metal or carbon of which the surfaces may for example be modified
("functionalized") so that biomolecules or antibodies can be attached to
them during the manufacturing process, wherein the biomolecules or
antibodies can be chosen e.g. to bind, again, specifically to cancer
cells or soluble tumor markers; (iii) membrane vesicles or micro or nano
particles with or without functionalized membrane surface, containing
dyes or markers or other agents in the lumen (in case of membrane
vesicles) or at their surface; or (iv) dissolved, emulsified or suspended
dyes or markers.

[0048]In a preferred embodiment the endoscopic device may further comprise
a drug application unit for the controllable release of a defined
quantity of a diagnostic and/or therapeutic drug or other agent into a
defined diagnostic and/or therapeutic target area.

[0049]In a preferred embodiment the endoscopic process may further
comprise the step of releasing a defined quantity of a diagnostic and/or
therapeutic drug or other agent into a defined diagnostic and/or
therapeutic target area by a drug application unit.

[0050]By using such drug application device, a defined quantity of a
diagnostic and/or therapeutic drug or other agent can be applied
specifically to a defined diagnostic and/or therapeutic target area,
minimizing the contamination of surrounding tissues and the impact on the
whole organism. Thus, a diagnostic agent (e.g. an extrinsic marker or a
dye or other substance) as mentioned above, or a therapeutic agent can be
dispensed pinpointedly to the defined diagnostic and/or therapeutic
target area that is to be diagnosed or treated, thereby potentially
achieving a better diagnostic result (e.g. by reducing the background
signal) and less exposure of surrounding tissue and the whole organism to
the applied agents (for example in case of using toxic dyes or
chemotherapeutics). This effect may even be improved when using agents
with functionalized surface regions, as explained above, which
specifically detect and attach to their targets.

[0051]Such drug application unit typically comprises three parts: (i) One
or more reservoirs in the eyepiece of the device where the diluted
ready-to-use diagnostic or therapeutic drug may be stored under
controlled environment conditions (cooling, light, gas atmosphere,
movement e.g. for holding colloids in suspense). (ii) One or more pumps
or micro-dispensers (and optionally valves) for conveying a defined
quantity of the drug wherein the pump(s) are connected to at least one
reservoir and (iii) one or more hollow, preferably flexible tubings
connected to the pump(s) that span substantially over the whole length of
the nosepiece alongside with the imaging fiber bundle from the eyepiece
to an outlet of the tubing in the nosepiece tip and through which the
drugs can be delivered. Optionally piezo or other types of
micro-dispensers instead of or in addition to the pumps may be localized
for example in the tip of the nosepiece. It is also possible to provide
the flexible tubing with a remotely controlled movable or extendable
outlet nozzle with or without a valve that can be moved to the desired
point of application for the drug. In some application cases, it can be
favorable not to install the tubing permanently inside the nosepiece, but
to introduce and advance the tubing in the working channel of the
nosepiece only temporarily for the purpose of drug application. By this
the tubing can be moved into and out of the nosepiece tip, e.g., by
simply pushing and pulling its eyepiece end. This flexibility has the
advantage that the tip of the tubing can be adjusted and monitored by the
imaging unit before the drug is applied.

[0052]In a preferred embodiment of the endoscopic device or process, the
therapeutic agent may comprise a drug being bound to or contained in a
drug carrier or an activatable inactive drug. By such embodiment it is
possible to bring the inactive diagnostic or therapeutic drug to the
intended diagnostic or therapeutic target area prior to releasing or
activating the drug in the target area for diagnosis or treatment which
may result in a better diagnostic result (e.g. by reducing the background
signal) and less exposure of surrounding tissue and the whole organism to
the applied agents (for example toxic dyes, chemotherapeutics).

[0053]For example it is possible to bind biochemical molecules or
particles to one or more drug molecules whereby the drug molecules are
rendered inactive. Another binding site of the biochemical molecule or
particle may be "functionalized" so that it may bind to specific cells
(e.g. cancer cells) or to another biomolecule or antibody that again
either binds specifically to the tissue to be treated (e.g. cancer
cells), or binds to an active transport system in cell membranes. As
another preferable possibility the drug molecules may be confined (either
morphologically, or just chemically inactivated) in the interior of a
"box" or "cage" like particle or in a membrane vesicle. Depending on the
particle design and manufacturing process, the outside can again be
functionalized with other biomolecules or antibodies that help to bring
the drug molecules to the specific target of application. In both cases,
the inactive drug may be linked or fixed almost completely for example to
the target cells prior to being activated. This activation may be induced
by irradiation with light or other electromagnetic radiation, by
excitation of mechanical vibrations of the box or cage molecule (e.g.
surface plasmons), or by chemical reactions.

[0054]A potentially huge advantage of such a local drug application is
that the total dose of the drug application, related to the whole
organism (e.g. the human body), is relatively small and specifically
localized to the pathologic tissue whereas healthy tissue is spared out.
That fact could allow the application of some highly effective drugs for
local application that have been ruled out for "global" chemotherapy due
to their side effects when systemically applied in therapeutically
effective doses.

[0055]In a preferred embodiment of the endoscopic device or process the
therapeutic drug may be releasable or activatable by irradiation with
laser light. This represents a very effective method for specifically
releasing or activating the inactivated drug in the target area.

[0056]The "box" or "cage" like particle or the membrane vesicle can be
designed so that they break apart upon irradiation with light of a
certain wavelength that is tuned to an absorption peak of the box or cage
or vesicle. Preferably the "box" or "cage" like particles or the membrane
vesicles exhibit a high peak in their optical absorption spectrum in a
spectral range where cells and intrinsic biomolecules have low
absorption.

[0057]It is feasible to use either the laser spot of the bioanalytical
unit but typically with higher intensity, or a specific second laser unit
which is not used for bioanalytical detection, wherein the laser spot for
the drug activation or drug release to the therapeutic target area may be
adjusted under visual control of the imaging unit.

[0058]In a preferred embodiment the endoscopic device may further comprise
a therapeutic unit for treating and/or destroying and/or removing tissue
from the therapeutic target area, preferably by releasing or activating a
therapeutic drug in a therapeutic target area through irradiation with
laser light, and/or by means of a surgical laser.

[0059]In a preferred embodiment the endoscopic process may further
comprise the steps of [0060]defining a therapeutic target area and
[0061]treating and/or destroying and/or removing tissue from the
therapeutic target area, preferably by means of releasing or activating a
therapeutic drug in a therapeutic target area through irradiation with
laser light, and/or by means of a surgical laser.

[0062]By such embodiment, for example, a pathological or cancerogenous
tissue can be treated immediately in connection with the first diagnostic
intervention directly through the endoscopic device, so that in many
cases another surgical invasion and a loss of time can be avoided.

[0063]This treating and/or destroying and/or removing tissue may be
achieved chemically by drug release to the therapeutic area as described
above. Furthermore classical surgical methods (e.g. using endoscopic
surgical instruments or thermocauter) may be applied. As a further
possibility a "surgical" laser capable of cutting biological tissue may
be provided in the endoscopic device. Unlike all other laser sources
mentioned above that are usually low to medium average power cw
(continuous wave) lasers, pulsed laser sources with high average power
and medium to low repetition rates are preferably used for this purpose.

[0064]Technically, it may be feasible, however, to use a common laser
source for surgery and spectroscopic measurements and/or release of
drugs, wherein the output power is attenuated when the laser is used for
spectroscopic measurements or release of drugs.

[0065]It may be furthermore advantageous to apply nanoparticles by the
drug application device to the area to be treated prior to laser surgery.
These nanoparticles may exhibit an absorption spectrum with a high
absorption peak in a spectral range where cells and natural biomolecules
have low absorption. Furthermore, the surface of the particles may be
functionalized to attach to cancer cells as described above. Upon laser
irradiation with the wavelength of an absorption peak of the
nanoparticles the energy is absorbed by the particles which heat up and
destroy the tissue around them whereas the tissue without particles
remains without harm (the particles effectively act as laser cutting
agent). In cases of certain tumors, it may be favorable to combine local
drug application and laser treatment in order to increase the success
rate and to minimize side effects for the patient. As a further aspect,
it may be possible to control the therapeutic result by the bioanalytical
unit immediately after the treatment.

[0066]As is typical for endoscopes, the endoscopic device of this
embodiment is divided into two parts or portions: the flexible nosepiece
which is introduced into a natural or artificial cavity or orifices of a
human body, and the eyepiece.

[0067]As can be seen in FIG. 1, the nosepiece comprises an optical fiber
bundle 2 for transmitting the endoscopic image of the examination area 1
in the interior of the human body which image is projected by a
collimating lens to the aperture of the optical fiber bundle 2. Each
fiber of the optical fiber bundle 2 gathers and transmits one pixel of
this image from the tip of the nosepiece to the eyepiece (not shown)
where the image is converted to electrical signals by a light sensitive
area sensor, like, e.g., a CCD or CMOS sensor. This optical fiber bundle
2 is coaxially surrounded by an outer protection shell 6 which is
radially spaced apart from the optical fiber bundle 2. In the space
between the optical fiber bundle 2 and the outer protection shell 6
several thin tubular structures are arranged which also substantially
span from the tip of the nosepiece to the eyepiece:

(i) Reference sign 3 denotes the optical fiber 3 of the SPR sensor which
is part of the bioanalytical unit and analyzes at least one physiological
or pathological parameter (e.g. a tumor marker). The cladding of the
optical fiber 3 is removed in an annular region 7 near the end of the
optical fiber 3 and replaced by a gold coating decorated with linker
molecules (e.g. antibodies for the tumor marker). Light that is coupled
into the optical fiber at the eyepiece will be transmitted to this coated
region where it is totally reflected by the inner side of the gold
coating, giving rise to an SPR signal generated upon binding of
respective molecules to the linker molecules at the outer surface. The
end face 8 of the fiber is reflective so that the light is returned to
the eyepiece where the SPR signal can be analyzed. Typically such SPR
sensor must be replaced after each measurement. To achieve this, the
whole optical fiber may be removed and a new fiber with a readily
prepared SPR sensor surface may be inserted.(ii) Reference sign 4 marks a
flexible tubing of the drug application unit by which e.g. dyes, marker
solutions or therapeutic drugs can be applied selectively to a desired
target region as described above. This flexible tubing of the drug
application unit is advanceable and retractable in a separate channel
formed in the nosepiece.(iii) Reference sign 5 denotes an optical fiber
for optical scanning spectroscopy which can be used for example for
conventional reflection spectroscopy, for fluorescence spectroscopy and
for Raman spectroscopy: The laser light of a spectrally tunable
continuous wave or pulsed laser transmitted by the optical fiber 5 is
focused by a lens and deflected e.g. by a small micro-optical
electromechanical system (MOEMS) device comprising a prism and two
adjustable micro-mirrors 9 so that the focused laser beam can raster scan
the whole area of interest. The spectroscopic signals are collected and
returned for measurement either via the same optical path as the
excitation light, or via the optical fiber bundle 2.(iv) Reference sign
10 identifies a small optical fiber bundle 10 of an in-situ sensor
(chemo-optical sensor) with several optical fibers of which the end faces
are coated with fluorescent molecular probes monitoring the presence,
absence, concentration, and/or modification of an effector (for example
pH, oxygen concentration, inorganic molecules, organic molecules or
biomolecules) which specifically interacts with said fluorescent
molecular probe, or with fluorescent antibodies e.g. for biomarkers,
wherein each of the fibers is coated with a different type of molecular
probe or antibody. Excitation light of a laser source, or a laser diode
or a LED (light emitting diode) is guided from the eyepiece through each
optical fiber and stimulates fluorescence of the molecular probes or
antibodies depending on the presence, absence, concentration, and/or
modification of the monitored molecule. The fluorescence signal returns
to the eyepiece via the same optical path as the excitation light where
this signal is analyzed.(v) Reference sign 11 indicates an optical fiber
11 for the surgical laser with focusing lens and a device 12 for
directing and adjusting the focused laser spot to the tissue to be
destroyed.(vi) A working channel 13 admitting the temporary introduction
e.g. of different surgical instruments or analytical equipment or probes
of the bioanalytical unit,(vii) a gas insufflator tube 14 for inflating
hollow organs and cavities in the body, an irrigator tube for rinsing the
examination area with physiological saline, a suction pump for removing
mucus, diagnostic or therapeutic drugs, or blood or tissue debris and a
coagulator for hemostasis (all not shown) may optionally be present in
the nosepiece.(viii) Optionally chemo-electrical sensors or transducers
15, such as electrochemical sensors, piezoelectric sensors or
semiconductor sensors, measuring further chemical or physical parameters
may be accommodated in the tip of the nosepiece and electrically
connected to evaluation electronics in the eyepiece. The structures
mentioned above, in particular sensory equipment or drug application
tubes may be present once, severalfold or absent in the endoscopic
device. Preferably the endoscopic device comprises one or more
bioanalytical units which offer a plurality of complementary analytical
methods which may help to reduce or eliminate artifacts and
wrong-positive and/or wrong-negative diagnoses. Furthermore, by this
approach reliable differential diagnoses may be rendered possible. The
skilled person will recognize immediately that the structures or modules
described above (items (i) to (viii)) are optional (meaning that they may
be present once, severalfold (e.g. different types of sensors) or absent)
and merely represent an exemplary combination that may be adapted e.g. to
the medical and diagnostic requirements of the intended application by
e.g. selecting an appropriate combination of the required or useful
modules.

[0068]The eyepiece substantially comprises the large and bulky or heat
producing components of the imaging unit and the bioanalytical unit which
cannot be accommodated inside the nosepiece. Amongst others, the eyepiece
of this embodiment contains e.g. the light sources (a gas discharge lamp
or a LED (light emitting diodes) or LED arrays for illuminating the
bright field endoscopic image, one or more spectrally tunable continuous
wave or pulsed lasers for spectroscopic analysis and for activating or
releasing drugs in the diagnostic or therapeutic target area and a pulsed
surgical laser source for cutting and ablating pathological tissue).

[0069]Furthermore, the eyepiece contains the opto-electronic sensor
converting the optical endoscopic image transmitted by the optical fiber
bundle into an electronic signal which is digitally enhanced and analyzed
by an image processing unit prior to being displayed preferably in real
time on a monitor and optionally parallelly recorded on a mass storage
device such as a hard disk. The eyepiece typically also contains a
spectral analyzing device for analyzing the signals of the scanning
optical spectroscopy. Additionally the eyepiece accommodates optical
sensors and analysis electronics for analyzing the optical signals of the
chemo-optical transducers and the SPR sensors. Besides, drug reservoirs
and pumps for the drug application device are also located in the
eyepiece.

[0070]In an alternative embodiment, the nosepiece of the endoscopic device
has a smaller diameter and is designed to enter the working channel of a
"conventional" medical endoscope. With this approach, two imaging units
(one of the conventional endoscope and one of the endoscopic device) can
be used in parallel. Such embodiment may even be more advantageous than
using a stand-alone endoscopic device, as the medical professional can
work with the endoscope he is familiar with (conversant with the
endoscope handling) and is supplied with the well-known information, but
supplementary with additional, independent information. Moreover the
medical professional can, e.g., control the current position of the
nosepiece within the field of interest. As a further positive aspect,
most doctor's offices and hospitals are already equipped with several,
specifically adapted medical endoscopes which are chosen and applied
depending on the diagnostic task, organ system and position of the area
to be examined and on the body size of the patient (e.g. adults or
children). It is readily apparent that this type of endoscopes can be
used with a variety of conventional endoscopes by which prime costs for
buying several endoscopic devices with extensive bioanalytical facilities
can be saved. In a further alternative embodiment the bioanalytical unit
is not fixedly integrated into the nosepiece but is advanced only
temporarily through the working channel offering the possibility to
choose the bioanalytical module depending on the medical task or to add
further bioanalytical modules at a later time for completing the
diagnostic facilities (depending on the available budget or the technical
development of improved analytical modules). As a further option, it is
conceivable to transmit the digital image data of the endoscopic image
together with the analytic results of the bioanalytical unit to a remote
medical competence center (e.g. via a secured internet connection) which
may assist a less experienced medical professional or a medical
professional who is not trained in this method (e.g. in emergency
departments, field hospitals, hospitals in developing countries), in
making complicated differential diagnoses or discussing difficult medical
decisions with a second expert, for example when deciding for an
immediate chemotherapeutic or surgical intervention by the means (e.g.
drug application unit, surgical laser) provided by this endoscopic
device.

[0071]In the following some general considerations are given concerning
further preferred embodiments of the endoscopic device according to this
invention:

[0072]The endoscopic device generally comprises at least one imaging unit
and at least one bioanalytical unit. The imaging unit relays an image
(still image, intervallic image sequence or movie) of the examination
area in the interior of the organism to the eyepiece, where the image is
typically converted by a camera (e.g. with CCD or CMOS sensor) and
electronically processed and displayed on a monitor for observation by
the medical professional. The imaging unit usually comprises a
collimating lens at the nosepiece end projecting an image of the
examination area to the aperture of a coherent bundle of optical fibers
within the nosepiece for transmitting the signal light to the eyepiece.
Instead of the optical fiber bundle, the image transmission may as well
be realized with a chain of relay optics made from, e.g., GRIN (gradient
index) lenses distributed over the length of the nosepiece.

(i) First, the imaging unit generates a visually observable image (or a
movie) of the examination area within the human body, e.g. under white
light illumination, that is used by the medical professional to orientate
himself or herself and to allow a medical examination of the area by
eye.(ii) Second, the imaging unit may be provided with facilities for
generating a visually observable image of the examination area by means
of other contrast methods, such as dark field, polarization, phase
contrast, differential interference contrast (DIC), confocal scanning
methods, or spectral analysis methods which may allow or increase
visibility of certain details in the examination area and/or improve
diagnostic assessment. Furthermore, other optical methods like widefield
fluorescence, Raman scattering, or nonlinear effects like multi photon
fluorescence, fluorescence lifetime measurement, or harmonic signal
generation imaging may also be implemented in an imaging mode of
operation provided by the imaging unit. In particular in case of Raman
spectroscopy, but also in some cases of fluorescence spectroscopy, high
excitation light power densities are necessary for sufficient signal
generation so that preferably one or more laser spots raster scan the
examination area, wherein the final observable image is electronically
recomposed from the gathered signal of the individual raster scanned
pixels. Such image generation by other contrast methods may help the
medical professional to recognize different tissue types or identify
pathological alterations of tissue, wherein the medical professional may
choose one or combine several image generation methods which fit best for
the specific diagnostic requirements.(iii) Third, the imaging unit may be
used to control the area of interest (which may be a fixed or freely
definable part of the examination area or may comprise the whole
examination area) within the area of examination in which the
bioanalytical unit is carrying out a measurement of physiological or
pathological parameters. When using spectroscopical methods for the
measurement of physiological or pathological parameters it may simply be
possible to visually observe the spot of focused light of the excitation
light source in the examination area by the endoscopic image of the
imaging unit. When applying sensor probes (e.g. chemo-optical or
chemo-electrical sensors or SPR sensors), the imaging unit may display
the tip of the sensor probe within the endoscopic image of the imaging
unit whereby the medical professional is capable to localize and adjust
the measuring spot of this sensor in relation to the anatomical
structures of the examination area.(iv) Finally, some structural
components of the imaging unit may be used to transmit excitation light
and recollect signal light for the spectroscopic analysis of a
physiological or pathological parameter carried out by the bioanalytical
unit. This could be realized as described below:

[0074]Excitation light source for the spectroscopic analysis (for example
a laser source, a laser diode, a light emitting diode (LED), an arc lamp
or gas discharge lamp with or without bandpass filter or monochromator),
light detector (spectrally integrating detector like, a photomultiplier
tube or a photo diode or a spectral analyzing detector, such as a light
spectrometer), and conventional or dichroic beam combiners and
splitters--all being part of the bioanalytical unit--are accommodated
within the eyepiece. The excitation light is coupled by the conventional
or dichroic beam combiner into one or a few or all fibers of the optical
fiber bundle of the imaging unit and projected to the area of interest.
The collected signal light evoked by the excitation light is again
transmitted via the optical fiber bundle of the imaging unit and coupled
out by the beam splitter and supplied to the light sensor of the
bioanalytical unit which resides within the eyepiece. Alternatively the
excitation light may be transmitted via a separate optical path, e.g., a
single-mode optical fiber preserving the ability to generate a tightly
focused laser spot, or a multimode fiber or a liquid light guide, which
can be mounted inside the nosepiece in parallel with the optical fiber
bundle of the imaging unit.

[0075]Amongst others, the bioanalytical unit may operate in two different
spectroscopic modes, both essentially relying on the same spectroscopic
methods: (i) in a sample mode, a physiological or pathological parameter
is analyzed in a two- (or three-) dimensional area or volume of the
sample (analyzed molecules are distributed in the sample volume which is
captured), and (ii) in a sensor mode, the physiological or pathological
parameter is measured directly at an active surface of the sensor e.g. by
a chemo-optical or SPR sensor at a selective spot of the sensor mounted
at the tip of the nosepiece (analyzed molecules are interacting with the
active surface of the sensor).

(i) In the sample mode, the excitation light exits from the fiber,
potentially passes some collimation lens and is directed into the sample
area (or volume), for example in the center of the field of view of the
imaging unit. This can be accomplished for example with mirrors that are
fixedly mounted at the nosepiece tip, so that the light spot position
remains constant with respect to the nosepiece tip, and the area of
interest is adjusted by moving the nosepiece tip. Alternatively, a small
micro-optical electromechanical system (MOEMS) device can be used for
providing the capability of defining the area of interest independently
within the examination area displayed by the imaging unit without moving
the nosepiece tip and changing the endoscopic image.

[0076]At the sample area (or volume), the excitation light interacts with
either intrinsic or extrinsic markers being naturally present in or
beforehandly applied to the sample, and which markers are chosen or
designed to generate optical signals that depend on the state of a
specific physiological or pathological parameter of the sample. One
example for such markers may be an extrinsic marker for e.g. a specific
biomolecule or immunological target (for example a fluorescent dye linked
to an antibody that specifically binds to e.g. tumor cells), wherein upon
binding of said extrinsic marker to the appropriate target the
fluorescence emission spectrum of the marker is changed. Another example
may be an intrinsic marker naturally occurring in the sample which marker
may produce Raman shifted signals, being indicative of a change of a
certain physiological or pathological condition. A third example may be
the spectral reflectivity of the sample that can be used, e.g., for
angiogenesis measurement by determining the vascular density in the
tissue (being a hint for a tumor), e.g. via analysis of reflection
spectra of hemoglobin in blood capillaries.

[0077]The optical signals from the sample and/or the intrinsic or
extrinsic markers are collected by the optical fiber bundle of the
imaging unit, optically analyzed, as mentioned above, and converted into
a two- (or three-) dimensional image.

(ii) Spectroscopical methods can also be used in a sensor mode of the
bioanalytical unit which measures molecules interacting with the active
surface of a sensor and may be carried out by e.g. a chemo-optical or a
SPR sensor at a selective measuring spot of the sensor mounted at the tip
of the nosepiece. In this case the optical signal generation takes place
for example at an active surface of the optical fiber (SPR sensor) or at
the fiber tip (e.g. chemo-optical sensor). The signal light is reflected
back typically through the same optical fiber as the excitation light and
is optically analyzed as a matter of principle in the same way as
described for the sample mode.

[0078]As is evident to a person skilled in the art, the exemplified
embodiments are given for the purpose of illustrating and explaining the
invention and shall not be understood in a sense limiting the invention.
All specific embodiments described in this application shall be construed
as illustrative examples which do not represent the whole scope of the
invention, whereas the scope of protection is exclusively defined by the
claims. Furthermore, it will be understood by a person skilled in the art
that the features of all embodiments disclosed in the dependent claims
and in the description may be combined--individually or together with the
features of other embodiments--with the endoscopic device or endoscopic
process of the invention as far as they are not mutually exclusive for
technical reasons.

Patent applications by Martin Vogel, Weinheim DE

Patent applications in class With tool carried on endoscope or auxillary channel therefore

Patent applications in all subclasses With tool carried on endoscope or auxillary channel therefore